Human SLE is well organized as a disease of relapses and remissions. However, the pathophysiology of relapse is poorly understood. Project 4 is designed to provide rigorous answers to the following key questions regarding the pathophysiology of SLE relapse: 1) What cause SLE relapse? It is widely believed that certain events such as psychological stress, infection, estrogens, or exposure to ultraviolent (UV) radiation can trigger SLE relapse: 1) What causes SLE relapse? It is widely believed that certain events such as psychological stress, infection, estrogens, or exposure to ultraviolet (UV) radiation can trigger SLE relapse. However, the evidence is largely anecdotal. 2) What determines severity of SLE relapse (e.g., why are some relapses renal relapses)? We hypothesize that the severity of relapse is determined by the strength of the trigger and/or the presence of certain "accelerators" of SLE relapse. However, the evidence is largely anecdotal. 2) What determines severity of SLE relapse (e.g., why are some relapses renal relapses)? We hypothesize that the severity of relapse is determined by the strength of the trigger and/or the presence of certain "accelerators" of SLE relapse. Accelerators could include acquired factors such as high expression of chemokines or leukotrienes. Accelerators could also be genetic factors such as dysfunctional CR1, an abnormally high dose of CR genes, or a mutated chemokine that has enhanced inflammatory effects. 3) Can SLE relapse be accurately predicted? Developing a practical statistical model for the early prediction of severe SLE relapse would be a great advance in the management of SLE. The design of Project 4 is straightforward. SLE patients with relapsing disease (N=100, 50 with renal involvement and 50 who never had renal involvement) will be characterized genetically and immunologically by Projects 1, 2, and 3, and will be meticulously followed with regular measures of the putative triggers and accelerators of SLE relapse. More than 300 relapses are expected during the 5 years of follow-up in Project 4. Using logistic regressions we will identify the authentic risk factor for SLE relapse, its severity, and its prediction. Project 4 is unprecedented in breadth, depth, and scope of testing to identify genetic and clinical risk factors for human SLE nephritis. Project 4 will help fulfill a major unmet need in our understanding of human SLE and its nephritis.